骨肉瘤患者3种基因多态性与大剂量甲氨蝶呤不良反应相关性的Meta分析  

Meta-analysis of the Association of 3 Kinds of Gene Polymorphisms with High-dose Methotrexate-induced ADR in Osteosarcoma Patients

作　　者：宋再伟 刘爽 易湛苗[1,2,3] 张恩瑶 赵荣生 SONG Zaiwei;LIU Shuang;YI Zhanmiao;ZHANG Enyao;ZHAO Rongsheng(Dept. of Pharmacy,Peking University Third Hospital,Beijing 100191,China;Dept. of Pharmacy Administration and Clinical Pharmacy,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China;Center for Drug Evaluation,Peking University Health Science Center,Beijing 100191,China)

机构地区：[1]北京大学第三医院药剂科,北京100191 [2]北京大学药学院药事管理与临床药学系,北京100191 [3]北京大学医学部药物评价中心,北京100191

出　　处：《中国药房》2019年第15期2135-2143,共9页China Pharmacy

基　　金：国家重点研发计划——纳米科技重点专项项目(No.2017YFA0205600)

摘　　要：目的:系统评价骨肉瘤患者亚甲基四氢叶酸还原酶(MTHFR)、还原性叶酸载体1(RFC1)、多药耐药基因1(MDR1)基因多态性对大剂量甲氨蝶呤不良反应的影响,为大剂量甲氨蝶呤临床个体化用药提供循证参考。方法:计算机检索Medline、Embase、clinical trials.gov、中国知网、万方数据和中国生物医学文献数据库,收集MTHFR C677T/A1298C、RFC1 G80A、MDR1 C3435T不同基因多态性与大剂量甲氨蝶呤不良反应相关性的队列研究,对符合纳入标准的临床研究进行资料提取后,采用纽卡斯尔-渥太华量表进行质量评价后,采用Rev Man 5.3、Microsoft Excel 2016对大剂量甲氨蝶呤相关不良反应(血液毒性与骨髓抑制、肝毒性、肾毒性、口腔黏膜炎、消化道毒性、整体不良事件)发生率等结局指标进行Meta分析与描述性分析。结果:共纳入8项队列研究,合计608例患者。报告MTHFR C677T、MTHFR A1298C、RFC1 G80A、MDR1 C3435T多态性相关的结局指标分别有6、5、4、2项。Meta分析与描述性分析结果表明,MTHFR C677T多态性与G3-4腎毒性[TT/CT vs.CC:OR=12.35,95%CI(3.28,46.42),P<0.001]、G3-4口腔黏膜炎[T vs.C:OR=2.04,95%CI(1.06,3.93),P=0.03]、口腔黏膜炎[TT vs.CT/CC:OR=2.27,95%CI(1.20,4.27),P=0.01]、肾毒性(P<0.05)的发生风险显著相关;MTHFR A1298C多态性与G3-4肝毒性、G3-4肾毒性、G3-4口腔黏膜炎有关,但均无显著相关性(P>0.05);RFC1 G80A多态性与血液毒性、肝毒性、肾毒性、消化道毒性均无显著相关性(P>0.05);MDR1C3435T多态性与口腔黏膜炎有显著相关性(P<0.05),与血液毒性、肝毒性均无显著相关性(P>0.05)。结论:MTHFR C677T突变可能导致大剂量甲氨蝶呤不良反应发生风险增加,MTHFR A1298C多态性与大剂量甲氨蝶呤不良反应无显著相关性,RFC1 G80A或MDR1 C3435T多态性与大剂量甲氨蝶呤不良反应的研究较少,相关性尚不明确。OBJECTIVE:To systematically evaluate the effects of MTHFR,RFC1 and MDR1 gene polymorphisms on highdose methotrexate-induced ADR in osteosarcoma patients,and to provide evidence-based reference for individual medication of high-dose of methotrexate.METHODS:Retrieved from Medline,Embase,clinical trials.gov,CNKI,Wanfang database and CBM,cohort studies about the association of MTHFR C677 T/A1298 C,RFCl G80 A,MDR1 C3435 T gene polymorphisms with high-dose methotrexate-induced ADR were collected.After data extraction of clinical studies met inclusion criteria,and quality evaluation with the Newcastle-Ottawa Scale,Meta-analysis and descriptive analysis were performed for outcome indexes as the incidence of high-dose methotrexate-induced ADR(hematotoxicity and myelosuppression,hepatotoxicity,nephrotoxicity,oral mucositis,digestive tract toxicity and overall adverse events)with Rev Man 5.3 and Microsoft Excel 2016 software.RESULTS:Totally 8 cohort studies involving 608 patients were included;6,5,4 and 2 studies reported outcome indexes related to MTHFR C677 T/A1298 C,RFC1 G80 A and MDR1 C3/435 T gene polymorphisms respectively.Meta-analysis and descriptive analysis showed that MTHFR C677 T gene polymorphism was significantly associated with the risk of G3-4 renal toxicity[TT/CT vs.CC:OR=12.35,95%CI=(3.28,46.42),P<0.001],G3-4 oral mucositis [T vs.C:OR=2.04,95%CI=(1.06,3.93),P=0.03],oral mucositis[(TT vs.CT/CC:OR=2.27,95%CI=(1.20,4.27),P=0.01]and renal toxicity(P<0.05);MTHFR A1298 C gene polymorphism was associated with G3-4 hepatotoxicity,G3-4 nephrotoxicity and G3-4 oral mucositis,without statistical significance(P>0.05).There was no significant correlation between RFCl G80 A polymorphism and hemotoxicity,hepatotoxicity,nephrotoxicity and digestive tract toxicity(P>0.05).MDR1 C3435 T polymorphism was significantly correlated with oral mucositis(P<0.05),but not with hematotoxicity and hepatotoxicity(P>0.05).CONCLUSIONS:MTHFR C677 T mutation can increase the risk of high-dose methotrexate-induced ADR.There is no significant

关 键 词：大剂量甲氨蝶呤 不良反应 骨肉瘤 基因多态性 META分析 

分 类 号：R738.1[医药卫生—肿瘤] R979.1[医药卫生—临床医学]